Maternal nutrition and oocyte programming

 描述（由申请人提供）：肥胖目前影响美国超过三分之一的育龄妇女，导致整体健康和代谢紊乱，包括生殖功能。肥胖女性生育能力低下和不孕的几率更高，但更重要的是，当她们怀孕时，她们的后代会遭受严重的健康后果。肥胖妇女的后代比正常体重妇女所生的后代更有可能在一岁时肥胖;在年幼时患有代谢综合征，高血压和肝病;并经历发育迟缓，智力残疾和自闭症谱系障碍。鉴于肥胖流行的严重性和棘手性，我们必须确定有效的干预手段，以防止这些不利影响的孕产妇肥胖，这需要确定的潜在机制。在本提案中，我们计划确定母体饮食诱导的肥胖如何通过卵母细胞编程影响下一代的后代。在目标1中，我们计划研究卵母细胞中TCA循环组分的代谢变化是否以及如何导致线粒体吞噬失调。我们将为这种卵母细胞现象建立一个时间表，然后确定这些步骤中的每一步如何在后代中表现出来。通过触发、抑制和替换卵母细胞中线粒体自噬缺失的部分，我们希望描述这一通路在正常和异常卵母细胞中的作用。最后，使用不同的小鼠品系，我们将区分父系和母系mtDNA，并确定父系线粒体的消除是否受到干扰。在目标2中，我们解决了传递给后代的问题是起源于细胞核还是线粒体。利用两个关键的共同研究者的独特专业知识，我们将辨别是否发生了核或线粒体的表观遗传修饰。同样使用ST和CT的相互技术，我们将确定哪种细胞成分负责表型。最后，使用目标1中使用的相同的双菌株实验，我们将回答后代"坏"的起源的重要问题-剩余的或新制作的。在目标3中，我们测试了母体干预，特别是运动和饮食改变，可以逆转或挽救这些事件和后代结果的可能性。如果成功的话，这些发现将大大提高我们对疾病发展起源的理解，不仅对育龄妇女有效治疗和行为建议的时机，而且对性质都有影响。

 DESCRIPTION (provided by applicant): Obesity currently affects over one-third of reproductive-age women in the United States leading to overall health and metabolic disorders, including reproductive function. Obese women experience subfertility and infertility at greater rates but more importantly, when they do get pregnant, their offspring suffer significant health consequences. Offspring of obese women are more likely than those born to normal-weight women to be obese at one year of age; to have metabolic syndrome, hypertension, and liver disease as young children; and to experience developmental delay, intellectual disabilities, and autism spectrum disorder. Given the severity and intractability of the obesity epidemic, we must identify effective means of intervention to prevent these detrimental effects of maternal obesity; this requires determination of the underlying mechanisms. In this proposal, we plan to determine how maternal diet-induced obesity affects offspring in the next generation via oocyte programming. In Aim 1, we plan to examine if and how metabolic changes in TCA cycle components in the oocyte lead to mitophagic dysregulation. We will establish a timetable for this oocyte phenomenon and then determine how each of these steps manifests in the offspring. By triggering, inhibiting and replacing missing parts of mitophagy in the oocyte we hope to delineate the role of this pathway in normal and abnormal oocytes. Finally, using different mouse strains we will distinguish paternal from maternal mtDNA and determine if elimination of paternal mitochondrial is perturbed. In Aim 2, we tackle the question of whether the transmission to offspring is nuclear or mitochondrial in origin. Using the unique expertise of two key Co- Investigators, we will discern if epigenetic modifications, nuclear or mitochondrial, are occurring. Also using the reciprocal techniques of ST and CT we will determine which cellular constituent is responsible for the phenotype. Finally, using the same dual strain experiments used in Aim 1, we will answer the important question of the origin of the offspring "bad" mitochondria-left over or newly made. In Aim 3, we test the possibility that maternal interventions, specifically exercise and dietary changes, can reverse or rescue these events and offspring outcomes. If successful, these findings will greatly enhance our understanding of developmental origins of disease and will have implications for not only the timing, but also the nature, of effective therapeutic and behavioral recommendations for reproductive-age women.